Prognostic impact of bridge or neoadjuvant induction chemotherapy in patients with resected oral cavity cancer: A nationwide cohort study

Abstract Background While surgery remains the primary treatment for oral squamous cell carcinoma (OCSCC), induction chemotherapy (IC) can be used as a bridging or neoadjuvant therapy. This nationwide study in Taiwan examines the survival outcomes of OCSCC patients who received IC before surgery. Methods We analyzed data from 29,891 patients with OCSCC. Of these, 29,058 initially underwent surgery (OP group), whereas 833 received IC before surgery (IC + OP group). A propensity score (PS)‐matched analysis (4, 1 ratio, 3260 vs. 815 patients) was performed considering tumor subsite, sex, age, Charlson comorbidity index, clinical T1–T4b tumors, clinical N0–3 disease, and clinical stage I–IV. Results In the PS‐matched cohort, the 5‐year disease‐specific survival (DSS) and overall survival (OS) rates were 65% and 57%, respectively. When comparing the OP and IC + OP groups, the 5‐year DSS rates were 66% and 62%, respectively (p = 0.1162). Additionally, the 5‐year OS rates were 57% and 56%, respectively (p = 0.9917). No significant intergroup differences in survival were observed for specific subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease. However, for patients with pT4a tumors, the OP group demonstrated superior 5‐year outcomes compared to the IC + OP group, with a DSS of 62% versus 52% (p = 0.0006) and an OS of 53% versus 44% (p = 0.0060). Notably, patients with cT2–3, cN1, and c‐Stage II disease in the IC + OP group were significantly more likely to achieve pT0–1 status (p < 0.05). Conclusions Following PS matching, the IC + OP group generally exhibited similar prognosis to the OP group. However, for pT4a tumors, the OP group showed superior 5‐year outcomes. While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment.


| INTRODUCTION
The National Comprehensive Cancer Network (NCCN) guidelines recommend initial surgery, which may include neck dissection, as the primary treatment for oral cavity squamous cell carcinoma (OCSCC). 1 Depending on the presence of pathological risk factors, adjuvant chemoradiotherapy (CRT) or radiotherapy (RT) may follow the operation. 1,2In cases where tumors are initially unresectable, neoadjuvant induction chemotherapy (IC) can be administered.4][5][6] For patients experiencing delays in their surgical schedule, IC can also serve as a bridging treatment to prevent tumor growth during the waiting period.Furthermore, some patients and head and neck surgeons may opt for neoadjuvant IC to shrink the tumor size.8][9] However, it is important to note that the primary objective of neoadjuvant or bridging chemotherapy in OCSCC is to target the primary tumor rather than cervical lymph node involvement.Consequently, radical surgery and neck dissection are frequently required, particularly in advanced cases. 10,11After chemotherapy, a minority of patients may achieve either a complete or partial response 3,4,8,9,12 or even a pathological complete response (pCR). 7,11Expectedly, this group tends to have better survival outcomes compared to other patients.
A randomized trial involving 195 patients with resectable OCSCC compared upfront resection to 3 cycles of IC using cisplatin and 5-fluorouracil, followed by resection.Both groups received appropriate adjuvant therapy.Although no overall survival (OS) benefit was observed in the IC group, the need for mandibulectomy and/or postoperative RT was significantly reduced compared to the control arm. 10Instead of focusing on improving survival endpoints, pursuing less morbid surgical interventions or reducing the need for or intensity of adjuvant therapy could be potential justifications for using IC in OCSCC.
To our knowledge, no large studies have been published that directly compared the outcomes between patients with OCSCC who had undergone primary surgery (OP group) with those who had received bridging or neoadjuvant IC followed by surgery (IC + OP group).To address this gap, we conducted a nationwide study in Taiwan with three primary objectives.First, we sought to ascertain whether a survival difference exists between patients receiving primary surgery alone and those undergoing IC followed by surgery.Second, in the event that both groups demonstrate similar prognoses, we aimed to identify specific subgroups that exhibit divergent outcomes between these two treatment strategies.Finally, we endeavored to pinpoint patients who are more likely to respond favorably to IC, as this could potentially lead to reduced surgical morbidity and/or improved survival outcomes.

| Data sources
We sourced patient data from the "long-form" of the Taiwanese Cancer Registry Database (TCRD), which covers over 99% of Taiwanese patients diagnosed with OCSCC.However, the TCRD lacks data on specific chemotherapy protocols, tumor resectability, postoperative morbidity and its severity, residual disease following surgery, and salvage treatment for patients who experience disease recurrence.Survival outcome data were gathered from the Taiwanese National Health Insurance Research Dataset (TNHIRD).The study adheres to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines. 13,14he research protocol was approved by the Ethics Committee of Chang Gung Memorial Hospital (reference number: 201801398B0A3), which also granted a waiver for obtaining written informed consent.Selection was guided by the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes.The study flow chart (Figure 1) provides details about the inclusion and exclusion of cases.Patients were deemed ineligible if their medical records indicated any of the following: (1) prior history of cancer, (2) initial nonsurgical treatment, excluding cases where chemotherapy was followed by surgery, (3) unknown clinical stage, or (4) interval between IC and surgery of less than 30 days or more than 120 days.The final study cohort consisted of 29,891 patients, all of Taiwanese descent.As patient selection spanned from 2011 and 2020, tumor staging was performed according to the criteria outlined in the AJCC Staging Manual, Seventh Edition (2010) and Eighth Edition (2018).The Eighth Edition incorporates depth of invasion (DOI) and extranodal extension (ENE) into the staging process. 15Out of 29,891 OCSCC patients, 29,058 (97%) underwent initial surgery, while 833 (3%) received bridging or neoadjuvant IC.Subsequently, a propensity score (PS)-matched analysis (4, 1 ratio, 3260 vs. 815 patients) was implemented considering tumor subsite, sex, age, Charlson comorbidity index (CCI), clinical T1-T4b tumors, clinical N0-3 disease, and clinical stage I-IV.Pathological parameters-including margin status, tumor differentiation, pT status, pN status, and pStage-were not included in the PS matching process.Notably, DOI information was missing for 12% (3501/29058) of patients in the OP group and 77% (643/833) of patients in the IC + OP group.Given the substantial limitation posed by the incomplete DOI data, particularly in the IC + OP group, we deliberately excluded DOI as an analysis parameter in this study.The follow-up period was calculated from the day of surgery to either the patient's death or the conclusion of the study (December 2021).

| Data collection
We acquired study variables from the 2020 TCRD release and the 2021 TNHIRD release, and conducted final data analyses in May 2024.We obtained morbidity and mortality data related to OCSCC from the TNHIRD and used the extracted information to calculate disease-specific survival (DSS) and OS, respectively.The TCRD generally adheres to the guidelines delineated in the Standards for Oncology Registry Entry (STORE) manual. 16As per the STORE guidelines, data on disease recurrences were collected independently from the anatomical site (i.e., local, regional, or distant recurrences); furthermore, only the initial recurrence was documented.Each participating hospital transmitted the relevant information to the TCRD during the first and fifth years of patient follow-up.Consequently, the survival data were considered entirely reliable for the calculation of DSS and OS; however, this reliability did not extend to disease-free survival (DFS), which includes the analysis of local control, neck control, and distant metastases.

| Statistical analysis
We utilized the Kaplan-Meier method to generate survival curves, with the log-rank test applied for statistical comparisons.We applied univariable and multivariable Cox proportional hazards regression analyses to investigate the relationships between the study variables and survival outcomes.Using a stepwise selection method, we incorporated all parameters from the univariable analysis into the multivariable model.The findings are presented as hazard ratios (HRs) accompanied by their corresponding 95% confidence intervals (CIs).We considered two-tailed p values as significant when they were less than 0.05.

| Patient characteristics
Table 1 presents the general characteristics of patients in the OP and IC + OP groups.Before PS matching, the IC + OP group showed a significantly higher prevalence of several variables compared to the OP group, including: (1) tumors subsites other than the tongue and buccal mucosa, (2) male sex, (3) cT4a and cT4b tumors, (4) cN2 and cN3 disease, and (5) c-Stage IV.Notably, the IC + OP group had a lower CCI compared to the OP group.After PS matching for tumor subsite, sex, age, CCI, clinical Tstatus, clinical N disease, and clinical stage, the IC + OP group showed a significantly higher prevalence of several pathological variables compared to the OP group.These parameters included well-differentiated malignancies, pT0 and pT1 tumors, and p-Stage I disease.Interestingly, the IC + OP group had fewer patients receiving free flap reconstruction and CRT.

| Five-year survival rates
In the initial cohort of 29,891 patients, the 5-year survival outcomes were compared between the OP group and the IC + OP group.The DSS rate was 79% for the OP group and 62% for the IC + OP group (p < 0.0001, Figure 2A).In addition, the OS rate was 71% for the OP group and 56% for the IC + OP group (p < 0.0001, Figure 2B).In the propensity score-matched cohort of 4075 patients, the 5-year survival outcomes were again compared between the OP group and the IC + OP group.The DSS rate was 66% for the OP group and 62% for the IC + OP group (p = 0.1162, Figure 2C).Furthermore, the OS rate was 57% for the OP group and 56% for the IC + OP group (p = 0.9917).

| Factors influencing five-year survival outcomes for patients with pT4a tumors in the propensity score-matched cohort
Following PS matching, the pT4 tumor category comprised 1560 patients in the OP group and 314 patients in the IC + OP group.An analysis of the factors influencing the 5-year survival outcomes for patients with pT4a tumors is presented in Table 2.For DSS, statistically significant differences between groups were observed for the following variables: buccal subsite, male sex, margin status less than 5 mm, well-tomoderate tumor differentiation, and pN0 disease.In terms of OS, significant differences were noted for buccal subsite, male sex, positive margins, margin status less than 5 mm, well-differentiated tumors, and pN0 disease.
2.5 | Five-year survival rates for patients who achieved pathological complete response in the propensity score-matched cohort In the PS-matched cohort (Table 1), 45 patients successfully achieved a pCR (pT0N0).The 5-year DSS rate was 95% for patients who achieved pCR, compared to 60% for those who did not (n = 770; p = 0.0001).Similarly, the OS rate was 95% for patients who achieved pCR, compared to 54% for those who did not (p < 0.0001).

| Factors influencing pathological complete response (pT0N0) or pT0-1 status in the induction chemotherapy arm following propensity score matching
To identify subgroups that might benefit from IC, we conducted a comprehensive analysis of patients who achieved pCR (pT0N0) or pT0-1 status in the IC arm following PS matching (n = 815).The main findings are summarized in Table 3. Notably, 45 patients achieved pCR (pT0N0), whereas 770 did not.In addition, 222 patients achieved pT0-1 tumor status, while 593 did not.We identified several patient subgroups that derived significant benefit from IC (p < 0.05) in terms of achieving pT0-1 status, including those with cT2-3, cN1, and c-Stage II disease.Furthermore, certain subgroups demonstrated a trend towards benefiting from IC (p > 0.05), such as patients with tumors in the buccal subsite and female patients, when considering pT0-1 status.Notably, when evaluating pCR status, subgroups that might benefit from IC included those with tumors in the tongue and buccal subsites, female patients, and those with cT2-3, cN1, and c-Stage II disease.As anticipated, the achievement of pCR or pT0-1 status in the OP + IC group was associated with a reduced need for free flap reconstruction and adjuvant RT/CRT.

Cox regression analysis in the propensity score-matched cohort
The results from both univariable and multivariable analyses conducted on the PS-matched cohort are presented in  T A B L E 1 (Continued) Table 4.Both analyses indicated that undergoing IC + OP was not a significant risk factor for 5-year DSS and OS.

| DISCUSSION
In this PS-matched analysis, the IC + OP group included a higher proportion of patients with pT0-1 tumors and pstage I disease.Furthermore, 28.4% ([721-516]/721) of patients with stage IV disease experienced downstaging after IC.Although this did not confer a survival benefit, it did stratify patients for further adjuvant treatment.This indicates that IC predominantly impacts the primary tumor, rather than the neck nodal disease.This is also reflected in the fact that fewer patients in the IC + OP group required free flap reconstruction and fewer received postoperative CRT.While the 5-year outcomes for the OP group and the IC + OP group were comparable, we found that in pT4a tumors, the OP group had better 5-year outcomes than the IC + OP group, with DSS at 62% versus 52%, and OS at 53% versus 44%, respectively.IC has the potential to downstage unresectable bulky tumors to a resectable status, control tumor progression prior to surgery, preserve organs, and reduce the risk of distant metastases.Furthermore, the pathological response to chemotherapy can stratify further adjuvant treatment in high-risk patients prone to treatment failure. 174][5][6] Notably, IC plays a crucial role in reducing surgical morbidities, primarily by enabling preservation of oral organs through conservative surgery.Lee et al. 7 have previously shown that 70% (16/23) of patients with tongue SCC could undergo tongue conservation treatment following IC.Similarly, Abdelmeguid et al. 8 reported that 25% (15/60) of the OCSCC surgeries were less extensive than initially planned.Although the current study could not assess detailed data on conservative surgery rates, the PS-matched group revealed that fewer patients in the IC + OP group required free flap reconstruction.Consequently, it is reasonable to hypothesize that more conservative procedures would reduce the need for free flap reconstruction.In studies focusing on IC, groups with a pCR have consistently shown more favorable outcomes compared to other groups. 7,11The present study demonstrated that, in the PS-matched cohort, patients who achieved pCR exhibited superior DSS (95% vs. 60%) and OS (95% vs. 54%).However, due to the inherent limitations of this nationwide study-which are  also applicable to the Surveillance, Epidemiology, and End Results (SEER) and National Cancer Database (NCDB)-DFS cannot be accurately represented. 18,19Although pCR rates in small case studies of neoadjuvant IC appear high, ranging from 27% to 50%, the current investigation found a pCR rate of only 6%.This discrepancy may be due to the fact that not all patients received neoadjuvant chemotherapy.However, a notable constraint of this study is the inability to distinguish between patients who received IC as a bridging therapy or as a neoadjuvant therapy, due to the TCRD's lack of data on specific chemotherapy regimens.
As a result, we are unable to draw definitive conclusions on whether outcomes differed for patients who received systemic therapy as neoadjuvant or as bridge therapy.However, we have mitigated this limitation by excluding patients who received IC within the 30 days preceding surgery.It is plausible that this group of patients received oral chemotherapy with minimal influence on survival outcomes.Surprisingly, in this real-world practice study, more than 700 patients received IC within 30 days before surgery (Figure 1).In our study, a mere 1.6% (13/833) of patients in the IC + OP group had stage I disease.In contrast, 28.5% (8280/29058) of patients in the OP group had stage I disease.The precise reason for administering induction chemotherapy in patients with stage I tumors was not specified in the database.Potential explanations include initial patient refusal of surgery or a delayed surgical schedule.Notably, 23.6% (197/833) of patients in the IC + OP group had T4b tumors, whereas only 3.3% (965/29058) in the OP group harbored T4b malignancies.Despite the smaller proportion of T4b tumors in the OP group, it still had a larger number of surgical patients (n = 965) compared to the IC + OP group.It is important to highlight that the current treatment modalities for upfront surgery in T4b tumors remain controversial.The AJCC sixth edition, published in 2002, defined T4b OCSCC as an unresectable tumor.However, the AJCC seventh edition, released in 2010, modified the definition of T4b OCSCC to very advanced local disease.The most recent NCCN guidelines, updated in 2024, continue to recommend clinical trials or nonsurgical approaches for the treatment of T4b OCSCC tumors. 1 However, our previous study, published in 2007, demonstrated that resected T4b tumors located below the mandibular notch (infra-notch T4b, accounting for 85% of T4b tumors) had better survival outcomes compared to tumors above the notch (supra-notch T4b, accounting for 15% of T4b tumors).Specifically, the 5-year DFS rates were 65% for infra-notch T4b tumors and 14% for supra-notch T4b tumors (p = 0.0004). 20Based on these findings, we have since adopted a practice of performing routine upfront surgery for infra-notch T4b tumors in our patients.2][23] In another investigation we previously conducted on Taiwanese patients with T4b tumors, we found that primary surgery was performed in 66% (327/492) of clinical T4b (cT4b) OCSCC, with clinical N0-2 (cN0-2) cases showing a favorable prognosis. 24It is important to recognize that the decision to perform upfront surgery for T4b tumors is not only guided by the anatomical location but also depends on the resection and reconstruction capabilities of each head and neck surgical team.

Characteristic (n, %) Induction chemotherapy plus surgery
A meta-analysis of 27 randomized trials involving 2872 patients revealed that IC does not significantly improve OS, DSS, or distant metastasis rates.However, it did show a significant improvement in locoregional recurrence. 25nother meta-analysis, which compared two phase III randomized studies of IC followed by surgery with or without postoperative RT to surgery with or without postoperative RT, found no significant overall benefit in favor of IC regarding locoregional recurrence, disease-free survival, and OS rates.Nevertheless, a subgroup analysis of individual data from cN2 patients demonstrated a statistically significant OS benefit in favor of IC. 26 In the current study, we were unable to present an analysis of locoregional recurrence due to the inherent limitations of the TCRD.While no significant differences in terms of survival were observed in subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease, the OP group exhibited superior 5-year outcomes in the case of pT4a tumors.Several factors may explain the inferior outcomes observed in patients with pT4a tumors in the IC + OP group.These include well-differentiated tumors, the presence of lesions in the buccal subsite, male sex, and absence of nodal involvement.In the context of head and neck cancer, well-differentiated squamous cell carcinoma has been found to be relatively less sensitive to IC than poorly differentiated tumors. 27Recent advancements in next-generation sequencing (NGS) have revealed that mutations in the FAT1 gene and the subsequent activation of the Wnt/β-catenin signaling pathway may contribute to chemoresistance in well-differentiated squamous cell carcinoma compared to poorly differentiated tumors. 28With regard to tumor subsite, buccal cancer is known to be a highly aggressive form of OCSCC, often presenting with bulky volumes and a high rate of local recurrence. 29,30n general, buccal cancer is more prevalent in men and accounts for 4%-7% of all head and neck squamous cell carcinomas in the United States.2][33][34] While tobacco and alcohol consumption are the primary risk factors for buccal squamous cell carcinoma in the United States, the practice of betel quid chewing in Southeast Asia significantly contributes to the higher

Univariable analysis
Stepwise incidence of this malignancy.This is attributed to the chronic exposure of the buccal mucosa to carcinogens and the persistent local inflammation induced by betel quid chewing. 35This oral habit, which is more prevalent among men, may also explain the sex disparity in the prevalence of OCSCC at this specific subsite.Notably, NGS studies conducted in OCSCC patients from betel quid chewing endemic areas have revealed unique genetic mutations, affecting the USP9X, MLL4, ARID2, UNC13C, and TRPM3 genes, beyond the common pathogenic variants in the TP53, FAT1, CASP8, HRAS, and NOTCH1 genes. 36Interestingly, a specific mutation-based signature in OCSCC has been shown to predict outcomes in a Taiwanese study. 37These findings may help elucidate the mechanisms behind the observed chemoresistance and poorer outcomes in the IC + OP group compared to the OP group in patients with pT4a tumors.This suggests that more aggressive adjuvant therapy may be needed after surgery for this group of patients.The recent advent of innovative therapeutic strategies, such as targeted therapies and immune checkpoint inhibitors, has shown promising anti-cancer effects in the treatment of recurrent or metastatic head and neck squamous cell carcinomas. 38When these approaches are combined with IC or applied after surgery, they hold the potential to amplify treatment responses in patients with locally advanced OCSCC.If these strategies prove successful in clinical trials, they could lay the groundwork for more effective clinical management in the future.Although we attempted to identify subpopulations likely to respond to IC, our analysis revealed that only patients with cT2-3, cN1, and c-Stage II disease were more likely to achieve pT0-1 status.Notably, no subpopulation of OP + IC patients was found to significantly achieve pCR.It is important to acknowledge that we were unable to assess the potential confounding effect of human papillomavirus (HPV) infection status on our findings.0][41] Further investigation is warranted to elucidate the potential relationship between HPV infections and the timing of tumor relapse.This study has several limitations that should be considered.Firstly, being a registry-based nationwide investigation, it is prone to unmeasured confounding factors.These unaccounted factors could introduce bias, potentially affecting the validity of our results.Secondly, the study was conducted in a region with a high prevalence of betel nut chewing, a cultural practice that significantly contributes to a high occurrence of buccal SCC.This factor may limit the applicability of our findings to Western countries.Lastly, the absence of detailed information on specific chemotherapy regimens implies that the IC + OP group might include patients who received neoadjuvant and bridging therapy.It is important to note that induction chemotherapy and bridging chemotherapy are distinct forms of treatment.Unfortunately, due to the limitations of the available data, these two groups had to be combined in the current study, potentially obscuring any differences in outcomes between them.Although cisplatin-based chemotherapy regimens are a cornerstone of systemic treatment for head and neck cancer, 1 the lack of detailed information on the specific schemes employed in our study precluded an assessment of whether all patients received the same chemotherapy protocol.Consequently, we are unable to determine if variations in protocols might have influenced outcomes.

| CONCLUSIONS
In summary, this study, based on PS matching, showed that the IC + OP group benefits primarily from primary tumor regression rather than nodal regression.This group also had fewer patients requiring postoperative CRT and free flap reconstruction.While the survival rates of the IC + OP group were comparable to the OP group, this was not the case for the subgroup with pT4a tumors.These findings highlight the nuanced role of IC in managing OCSCC, suggesting its benefits may be tumor-stage specific.Future clinical trials could help enhance treatment responses in pT4a OCSCC.While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment.

F
I G U R E 2 Kaplan-Meier plots comparing disease-specific survival before (A, B) and after (C, D) propensity score matching in patients who initially underwent surgery (OP group) and those who received induction chemotherapy prior to surgery (IC + OP group).

F 3
I G U R E 3 Kaplan-Meier plots of disease-specific survival and overall survival for patients with pT4a (A, B), pT4b (C, D), and pN3 (E, F) tumors in the propensity score-matched cohort.T A B L E 2 General characteristics of patients with pT4a oral cavity squamous cell carcinoma who had undergone initial surgery versus bridge/neoadjuvant induction chemotherapy followed by surgery (n = 1874): Associations with 5-year clinical outcomes.General characteristics of propensity score-matched patients with oral cavity squamous cell carcinoma who had undergone bridge/neoadjuvant induction chemotherapy followed by surgery, stratified by pathological complete response (pT0N0) and pT0-1 tumor status.

T A B L E 1
General characteristics of patients with oral cavity squamous cell carcinoma who had undergone initial surgery versus bridge/neoadjuvant induction chemotherapy followed by surgery.

Characteristic (n, %) Original cohort Propensity score-matched cohort Initial surgery (n = 29,058) Induction chemotherapy plus surgery (n
Univariable and multivariable analyses of risk factors for 5-year disease-specific survival and overall survival in the propensity score-matched cohort. Abbreviations: CCI, Charlson comorbidity index; pCR, pathological complete response; SD, standard deviation; SMD, standardized mean difference.apT0:the initial biopsy results confirmed the presence of squamous cell carcinoma; however, subsequent surgery revealed no residual tumor tissue.T A B L E 3 (Continued)T A B L E 4